Kymera Therapeutics Presents Preclinical Data Demonstrating Activity of KT-253, a Selective Heterobifunctional Degrader of MDM2, in AML at American Society of Hematology Annual Meeting

  • A single dose of KT-253 induced rapid apoptosis and sustained tumor regression in xenograft models of AML
  • KT-253 showed combinatorial advantage with the BCL-2 inhibitor venetoclax in the venetoclax-resistant AML model
  • KT-253 is also active in other hematologic malignancies including DLBCL

WATERTOWN, Mass., Dec. 11, 2022 (GLOBE NEWSWIRE) — Kymera Therapeutics, Inc. (NASDAQ: KYMR), a clinical-stage biopharmaceutical company advancing targeted protein degradation to deliver novel small-molecule protein-degrading medicines, today presented preclinical data demonstrating that KT-253, a novel MDM2 degrader, inhibited tumor growth as a single agent and in combination with venetoclax in AML xenograft models. The data were presented at the American Society of Hematology (ASH) Annual Meeting, taking place December 10-13, 2022, in New Orleans, Louisiana.

Murine double minute oncoprotein 2 (MDM2) is the E3 ligase that ubiquitinates and degrades the tumor suppressor p53. While reversible small molecule inhibitors (SMIs) of the MDM2/p53 interaction have been developed to stabilize p53 in order to induce tumor cell death in p53 wildtype (WT) tumors, they induce a feedback loop that upregulates the protein MDM2 and thus reduces levels of p53 protein – limiting its biological activity and clinical application. Recent clinical trials with MDM2 inhibitors, particularly in relapsed/refractory acute myeloid leukemia (AML), have resulted in suboptimal clinical activity, highlighting the need for new therapeutic approaches for the treatment of hematological malignancies and WT p53 solid tumor. MDM2 degraders, thanks to their catalytic mechanism, can overcome the feedback loop and lead to a more efficient stabilization of p53 and the induction of an acute apoptotic response in tumor cells.

Kymera has previously demonstrated that KT-253, a novel highly potent and selective heterobifunctional MDM2 degrader, has superior activity compared to MDM2 SMIs and demonstrated greater than 200-fold improvements in both in vitro cell growth inhibition and apoptosis. Due to the distinct pharmacological profile compared to MDM2/p53 SMIs, a single dose of KT-253 was sufficient to induce rapid apoptosis and sustained tumor regression in MV4;11 AML and RS4;11 ALL cell line-derived mouse xenograft (CDX) Templates.

New results in AML now demonstrate that KT-253 administered once every three weeks led to tumor regression in the CTG-2227 AML patient-derived xenograft (PDX) model and responses in the CTG-2240 and CTG-2700 AML PDX models. These data support an intermittent dosing schedule of KT-253 in AML that has the potential to improve efficacy and safety using the degrader approach. Furthermore, in a CDX AML model resistant to the standard of care BCL-2 inhibitor venetoclax, KT-253 administered once every three weeks in combination with venetoclax achieved durable tumor regression. This suggests a potential benefit of KT-253 combined with the AML cure agent standard that could further expand the possibilities for development in AML.

KT-253 has also shown activity in additional hematologic malignancies, including both in vitro and in vivo single agent responses in DLBCL, supporting the development of KT-253 in additional indications such as lymphoma.

“Our KT-253 degrader, unlike small molecule inhibitors, has the potential to bypass the feedback loop that upregulates MDM2 production and more effectively stabilize the p53 tumor suppressor, alone and in combination with widely used treatments” said Nello Mainolfi, Ph.D., Cofounder, President and CEO, Kymera Therapeutics. “Given that dependence on P53 is present in a large number of tumor types, we are excited to advance this compound into clinical trials to evaluate its impact on the treatment of AML and other wild-type p53 cancers.”

Presentation at the ASH Annual Meeting:

  • Title: Development of KT-253, a highly potent and selective heterobifunctional MDM2 degrader for the treatment of acute myeloid leukemia

    • Abstract number: 2776
    • Session Time: 6:00pm – 8:00pm CT, December 11, 2022
    • Location: Ernest N. Morial Convention Center, Hall D
    • Presenter: Stefanie Schalm, Senior Director, Oncology, Biology, Kymera Therapeutics

About the MDM2 Degradation Program, KT-253

KT-253 is a potent and selective degrader of MDM2 with the potential to be a best-in-class p53 stabilizer. MDM2 degradation bypasses the feedback loop that regulates MDM2 production and, in doing so, more effectively drives cancer cells towards rapid apoptosis. Because wild-type p53 is present in over 50% of tumors, KT-253 represents another program with broad franchise potential in liquid and solid tumors. Kymera focuses on indications with specific sensitivity to this mechanism of action, such as AML, lymphoma and solid tumors through a targeted biomarker strategy. Kymera expects to clear an IND for KT-253 by Q4 2022.

About Kymera Therapeutics

Kymera Therapeutics (Nasdaq: KYMR) is a biopharmaceutical company pioneering the field of targeted protein degradation, a transformative approach to addressing disease targets and pathways inaccessible with conventional therapies. Kymera’s Pegasus platform is a powerful drug discovery engine, promoting new small-molecule therapies that harness the body’s innate protein recycling machinery to degrade disease-causing dysregulated proteins. With a focus on undoped nodes in validated pathways, Kymera is advancing a pipeline of new therapeutics designed to address the most intractable pathways and deliver new treatments for patients. Kymera’s initial programs target IRAK4, IRAKIMiD, and STAT3 within the IL-1R/TLR or JAK/STAT pathways, providing opportunities to treat patients with a broad range of immune-inflammatory diseases, hematologic malignancies, and solid tumors . For more information, visit www.kymeratx.com.

Founded in 2016, Kymera is headquartered in Watertown, Massachusetts. Kymera has been named a “Fierce 15” biotech company by Fierce Biotech and has been recognized by both the Boston Globe and the Boston Business Journal as one of Boston’s best places to work. For more information about our people, science and pipeline, visit www.kymeratx.com or follow us on Twitter or LinkedIn.

Cautionary Note Regarding Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, express and implied statements by Kymera Therapeutics regarding: strategy, business plans and objectives for IRAK4, IRAKIMiD degradation programs, STAT3 and MDM2; plans and timelines for the clinical development of its product candidates, including their therapeutic potential, clinical benefits, and safety; expectations regarding the timing, success and data announcements of currently ongoing clinical trials; the ability to initiate new clinical programs; and expected cash and trail location. The words “may”, “may”, “will”, “may”, “would”, “should”, “expect”, “plan”, “anticipate”, “intend”, “believe”, “expect”, “estimate”, “seek”, “foresee”, “future”, “project”, “potential”, “continue”, “target” and similar words or phrases are intended to identify forward-looking statements, although not all statements that watch contain these identifying words. Any forward-looking statements contained in this press release are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that could cause actual events or results to differ materially from those expressed or implied by any forward-looking statements. statements contained in this press release, including, without limitation, the risks associated with: the impact of COVID-19 on the countries or regions in which we operate or conduct business, as well as the timing and expected results of our current preclinical study; and future studies and clinical trials, future supply chain, strategy and operations; the delay of any current and future preclinical or clinical trials or drug candidate development of Kymera Therapeutics; the risk that the results of current preclinical studies and clinical trials may not be predictive of future outcomes in relation to future clinical trials; Kymera Therapeutics’ ability to successfully demonstrate the safety and efficacy of its drug candidates; the timing and outcome of Kymera Therapeutics’ planned interactions with regulatory authorities; obtain, maintain and protect your intellectual property; and Kymera Therapeutics’ relationships with its existing and future collaborative partners. These and other risks and uncertainties are described in greater detail in the section titled “Risk Factors” in the Annual Report on Form 10-K for the period ended December 31, 2021 and in the most recent Quarterly Report on Form 10-Q, as well as discussions on potential risks, uncertainties and other important factors in Kymera Therapeutics’ subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent the views of Kymera Therapeutics as of today’s date only and should not be relied upon as representing its views as of any subsequent date. Kymera Therapeutics explicitly disclaims any obligation to update any forward-looking statements. No representations or warranties (express or implied) are made as to the accuracy of any such forward-looking statements.

Investor contact:
Bruce Jacobs
Head of Finance
[email protected]
857-285-5300

Chris Brinzey
Managing Director, Westwicke
[email protected]
339-970-2843

Media contact:
Todd Cooper
Senior Vice President, Corporate Affairs
[email protected]
857-285-5300



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